Hemoglobin switching provides a prototypical system for studying the control of gene activity during human ontogeny and erythroid cell differentiation. One of the mechanisms that this is accomplished, involves silencing of the embryonic and fetal genes during certain periods of human differentiation. The aim of the present study is to characterize the silencer located 5' to the epsilon-globin gene, test its action on heterologous globin promoters and identify the DNA binding proteins, interacting with the silencer. Similar work will be carried out for a 5' A-gamma-gene silencer identified in transgenic mice. Understanding the molecular control of switching may allow for novel therapeutIc interventions related with fetal hemoglobin induction in patients with beta-thalassemia.